University of Windsor. Essex Hall Study. Final Report. Eric Mintz, PhD

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2 University of Windsor Essex Hall Study Final Report Eric Mintz, PhD September, 2008

3 Table of Contents Executive Summary...i 1. Background and Pilot Study...i 2. Methods...i 3. Results and Discussion...ii 4. Conclusions...v Main Report... 1 A. Background... 1 a. Introduction... 1 b. Pilot Study... 1 c. Possible Exposures... 1 d. Rationale for Further Study... 2 B. Literature Overview... 4 a. Definitions and Descriptive Epidemiology... 4 b. Etiology... 5 C. Methods... 7 a. Study Population... 8 D. Limitations a. General b. Study Specific Power considerations Data base irregularities Limited exposure data E. Sources of Bias a. Misclassification by disease b. Misclassification by exposure c. Migration d. standard rates e. Healthy Worker Effect F. Burden of Proof G. Results Background a. Characteristics of the study cohort i. Starting date ii. Person-Years b. Standard populations some considerations H. Results a. Interpretive Caution b. Entire Cohort i. All cancers combined (total cancer) ii. Individual Cancers of interest (males only) c. Analyses by workplace d. Analyses by start date - pre-post e. Analyses by start date - pre-post I. Discussion J. Conclusions References... 37

4 Executive Summary 1. Background and Pilot Study An apparent occupational cancer cluster is a perceived excess of cancer that appears in a work population or subgroup over a given time period. Often an investigation is initiated, as in this case, by a belief among workers that all or some of their coworkers are experiencing more than the normal amount of cancer. In 2003, the University of Windsor expressed concern about an apparently unusual number of cancers that had occurred in workers from South Essex Hall. A preliminary, pilot study, verified the initial cancers of concern by running the six involved names through the Cancer Care Ontario (CCO) Registry. The presence of cases of multiple myeloma, Waldenstrom's macroglobulemia and chronic myeloid leukemia (CML) warranted an epidemiological study. All three are uncommon disorders of blood cells originating in the bone marrow. While no general, pertinent occupational exposures can be verified, workers described the air quality as being very poor before the ventilation improvements were done in the 1990s, during an initial meeting with union representatives, and University of Windsor stakeholders. The building is located very close to the on ramp of the Ambassador Bridge. Due to heavy truck and auto traffic and slow speeds, exposure to exhaust, both diesel and gasoline, was thought by some workers to be very heavy, particularly in South Essex Hall. As well, there were several tool and die workers employed in South Essex Hall before Tool and die workers are exposed to metalworking fluids (MWFs) for which there is evidence linking them to several cancers (26). 2. Methods This is a historical cohort study where workers were identified by past employment records and followed forward in time, to trace cancer development. Standardized Incidence Ratios (SIRs) were calculated on the historical cohort of workers who started work in Essex Hall at any time between 1955 and Standardized Incidence Ratios (SIRs) were constructed for total cancers and individual cancers (or related groups of cancers) where numbers permitted. The person-years of exposure partitioned by age and sex were calculated using the human resource data base of workers in Essex Hall. Analyses were done using both Windsor-Essex 1986/1996 and Ontario age-specific cancer incident rates from 1986/1996 to calculate the expected number of cancers. i

5 The observed cancers were compared to the expected cancers using the SIR as follows: SIR = observed/expected where: observed - the number of cases of the cancer of interest that developed in the work cohort as ascertained from linkage with CCO records expected - the number of cancers that would have occurred in the worker population if they were getting cancer at the same rate as the standard population Therefore an SIR of 1 means that the worker population is getting cancer at the same rate as the standard population (Windsor-Essex or province of Ontario). We say that they are getting cancer at the expected rate. An SIR of 2 means that the worker population is getting cancer at twice the expected rate. They developed two cancers for every one expected. This signifies, of course, that there may be a problem. Analyses were done separately for those who worked in North Essex Hall and South Essex Hall. Similarly, SIRs were computed separately for those who started before 1990 (and 1985) and those that started work after those dates. Ninety percent approximate confidence intervals were calculated and presented for all SIRs (6). Study Population The study population was to comprise all of those who started work in Essex Hall during the time period of 1955 to The work roster was incomplete however, as those who began work before 1985 were included in the roster only if they were still actively working during 1985 or thereafter. These problems arose because only current workers were transferred to an updated human resources database in Results and Discussion Total Cancer Workers in the entire Essex Hall work cohort experienced cancer at only about 60% of the expected rates, based on either standard. These results were statistically significant at the 5% level, meaning we are quite sure that the SIRs are truly less than one. This ii

6 result held for both males and females, although the female results were not statistically significant, since they were based on much smaller numbers. Partitioning the data by starting date or work location in Essex Hall (for males only) produced similar results even though those who started work before 1985 or 1990 had higher SIRs than those who started work after those dates. Comparison of the early start group SIRs to the later start groups SIRs is dubious because the later groups were younger. Differences noted in the SIRs may be due to differences in the worker agedistribution or due to differing cancer risk of a combination of both. Workers in South Essex Hall showed slightly higher SIRs than those calculated for workers in North Essex Hall. An important question is why would the total cancer rates be so low? It is possible that there has been incomplete ascertainment of cancer cases for some reason, including high post retirement migration rates. Also, especially in the very recent past, CCOs records may not be complete..a major reason for the very low overall cancer rate is the large deficit of lung cancer from the expected rate. Workers in Essex Hall developed lung cancer at only about 20 percent of the standard rates. Stated differently, only about one lung cancer case developed for every five expected. This statistically significant finding is quite dramatic. Since we know that the large majority of lung cancers are attributable to smoking (16), it follows that smoking rates were probably very low in this cohort. If true, this low smoking rate could explain much of the departure from expected cancer rates, since smoking is a risk factor for several cancers besides lung cancer. Multiple Myeloma Only two cases of multiple myeloma occurred in this cohort However, since this is a relatively rare disease, even two cases constitute an somewhat unusual event statistically (p<.10) overall. Furthermore, one of the cases was actually Waldenstrom s which is an even rarer variant. This case occurred in a 37 year old man, while the vast majority of Waldenstrom s occurs in men over 60. Multiple myeloma is also a disease of older people having a similar, very steep risk curve with increasing age (13). Both myeloma cases occurred in South Essex Hall workers who started work before This is what we would expect if myeloma was associated with alleged exposures that were more marked before the late 1990s in South Essex Hall. The results of the study are consistent with an increased rate of multiple myeloma that is concordant with a relationship to work related exposures. It should be noted that the knowledge of the causes of multiple myeloma and Waldenstrom s are limited. But two suspected causes for multiple myeloma are radiation and diesel fume exposures, for which the evidence is more conclusive in support of radiation. Although some South Essex Hall workers related radiation exposures, the most pertinent, general exposure, although speculative, here is probably diesel fumes. iii

7 Ecological studies, such as this one, may establish associations between exposures and subsequent development of disease. Causal links are rarely established, because by definition no information is available regarding previous occupational exposures, lifestyle risk factors (e.g. smoking), family history, and other risk factors for disease. Only occasionally if there is good occupational hygiene history of a smoking gun (a well established exposure to a known cause of the disease being studied) and the results are very strong and consistent, a probable causal link may be inferred. The causal inference would require other causal criteria such as dose-response to be satisfied as well. But in this study there is no occupational hygiene data from the historical period in question. As well, diesel fumes are a suspected, but not an established causal factor for multiple myeloma. Furthermore, the data is very limited. The results of this study fall far short of being sufficient to establish a causative relationship between working in South Essex Hall and the development of multiple myeloma and Waldenstrom s. This study shows a statistical excess of multiple myeloma in South Essex Hall. If Waldenstrom s was analysed separately then Waldenstrom s showed a strong statistical excess. No matter how these cases were divided, the development of these two cases in this work cohort was a somewhat uncommon event statistically. The evidence is far too limited, however, to infer a causal link, although one may exist. There are three possible explanations for the statistical excess of multiple myeloma. 1. The results occurred by chance, even though they are statistically significant. The precise probability of getting this result by chance is not possible to determine for the reasons outlined in this report. 2. There is a true excess, but it is not related to exposures in Essex Hall. One or both of the workers in question may have been exposed in prior occupational or medical settings or as part of their lifestyles. They may also have a predisposition to develop these cancers. 3. There is a true excess and it is related to occupational exposures in South Essex Hall. These exposures may be general, experienced by most or all workers in South Essex Hall or they may be more limited, for example, to tool and die workers. Since we lack historical occupational hygiene data, etiological research for multiple myeloma has not strongly pointed to specific causes and we have very limited data, which is insufficient to further investigate causation, it is not possible to determine which of these scenarios is most likely. Chronic Myeloid Leukemia (CML) Only one case of CML developed in this cohort, however, it is a somewhat unusual statistical event, as well, particularly when the more stable Ontario standard rates were used. Although CML is a distinct condition, Waldenstrom s and multiple myeloma are iv

8 similar in that they are all disorders of blood cells originating in the bone marrow. The development of these three rare cancers, that share important characteristics, taken together, is suggestive of pertinent exposures. Furthermore, all three cancers occurred in men who started work in South Essex Hall workers who started before The evidence is not nearly sufficient, however, to infer a causal link to exposures in South Essex Hall, for reasons discussed earlier. Pattern The pattern of cancer development in this cohort differed from the expected pattern. Only about 2.5% of all cancers that developed were expected to be either myeloma or CML, using the expected values computed from the Windsor-Essex standard (Table 3). These rarer cancers, however, actually accounted for 11.1% (3/27) of the cancers that developed in the work cohort. The common cancers, lung and colon cancer, were expected to account for 29.4% of total cancers. However, they also accounted for only 11.1% (3/27) of the observed cancers. There was a marked excess of the three rarer cancers over the expected and a clear deficit of these two common cancers. Although, these proportions are not independent, the pattern is unusual, for these rare and related cancers to have the same incidence as the two common cancers. Tool and Die Work There were 10 confirmed tool and die workers who started work in South Essex Hall before Two of the three rare cancers of interest occurred in this small group. While this result may have been a chance event, it may also be due to exposures to metalworking fluids (MWFs) encountered by these workers. While some MWFs are established carcinogens, the evidence for a link to the rare cancers encountered here is presently equivocal (26). Along with the very small number of these workers and the lack of knowledge regarding specific exposures that these workers encountered, it is not possible to determine if the excess of these rare cancers was due primary to MWF exposures. 4. Conclusions 1. The total (all cancers combined) cancer rates experienced by Essex Hall workers who began work between 1955 and 2005, was dramatically lower than the cancer rates of the general population of Windsor-Essex (p<.05). In fact, these workers developed cancer at only ½ to 2/3 the rate of the Windsor-Essex standard population. 2. Male total cancer rates held at two thirds of the standard rates or less, regardless of whether they worked in South or North Essex Hall. 3. Male total cancer rates held at two thirds of the standard rates or less, regardless of whether they started work before or after It follows from 1. to 3. above that the results of this study do not support any excess of total cancer in this work group. In fact, they point more to a deficit of total cancer. v

9 5. It is very unlikely that the Healthy Worker Effect (HWE) explains a large portion of the low cancer rates described in 1. to 3. above. 6. Male lung cancer rates, for the entire cohort, were found to be only about 20 percent of expected rates (p<.05). Stated differently, Essex Hall male workers developed only 1 lung cancer for every 5 lung cancers that occurred in similar males in Windsor- Essex. 7. Since smoking is a dominant cause of lung cancer, it is a reasonable implication that this cohort of workers had low smoking rates. The reason for these low rates is not known but may be due to ethno-cultural factors or socioeconomic or other factors. 8. Since smoking is also causally related to many other cancers, low smoking rates likely contribute to most of the deficit of cancer that developed in the cohort. 9. Ecological studies, such as this one, are blunt tools and therefore do not generally provide strong evidence for a causative relationship between an exposure and disease. This is particularly true, since there is no smoking gun in this study. A smoking gun is a well-established causal factor for a disease that workers were known to be exposed. 10. Although SIRs for prostate cancer generally showed a slight elevation, none was statistically significant. Those who started working in Essex Hall before 1985 had the highest SIR. There were not many person-years in the highest risk age groups for prostate cancer in the post 1985 start date group making comparisons to the earlier start date group somewhat tenuous. 11. The small number of recorded workers who started work before 1985 hamper somewhat the ability of the study to evaluate exposures in Essex Hall. It is also evident that since some cancers can take up to 25 years to develop, that follow-up time may not be sufficient to identify many work related cancers in workers who started after 1985 and particularly after The records of many workers who started work before 1985 were unavailable for analyses which added additional uncertainty to interpretation of study results. 13. It is difficult to decide how best to classify the Waldenstrom s case given the circumstances outlined in the report. The development of even one Waldenstrom s in a group this size is unexpected, as it is an extremely rare condition. When analysed separately, the Waldenstrom s SIR was very high at more than 23 (p<.05). This high SIR is due to the rareness of Waldenstrom s. 14. This study shows a statistical significant excess of multiple myeloma (when the Waldenstrom s was counted as a myeloma) in South Essex Hall that was consistent with a causal link to exposures in South Essex Hall. The sum of the statistical and exposure data is too weak to differentiate between the possibilities that the excess of multiple myeloma was a chance finding, was a true finding but not due to Essex Hall exposures, or a true finding due to Essex Hall exposures. 15. Whether the Waldenstrom s was analysed separately or as a myeloma, the occurrence of these two rare cancers was a somewhat unusual statistical event. 16. Although only one case of CML developed in this cohort, it is a somewhat unusual statistical event, as well, particularly when the more stable Ontario standard rates vi

10 were used. Although CML is a distinct condition, Waldenstrom s and multiple myeloma are similar in that they are all disorders of blood cells originating in the bone marrow. The development of these three rare cancers, that share important characteristics, taken together, is suggestive of pertinent exposures. Furthermore, all three cancers occurred in men who started work in South Essex Hall workers who started before The evidence is not nearly sufficient, however, to infer a causal link to exposures in South Essex Hall. 17. The pattern of cancer development was unusual in this cohort as the number of the three rarer tumours originating in the bone marrow was equal to the number of the much more common lung and colon cancers. Although they are not independent, the proportion of total cancers that were due to the three rarer tumours was much greater than expected while the proportion of the common cancers was far smaller. 18. The study results suggest that MWF exposures experienced by tool and die workers, may have been largely responsible for the excess of rare cancers noted. The evidence supporting a causal link between tool and die work and the rare cancers, however, is weak and circumstantial. Conclusions are limited by the small number of relevant tool and die workers, and the limited knowledge about the relationship between MWF exposures from this time period and the rare cancers found in this study. Additionally, none of the tool and die workers developed a cancer that is strongly linked to MWFs in the scientific literature. vii

11 Main Report A. Background a. Introduction An apparent occupational cancer cluster is a perceived excess of cancer that appears in a work population or subgroup over a given time period. Often an investigation is initiated, as in this case, by a belief among workers that all or some of their coworkers are experiencing more than the normal amount of cancer. In 2003, the University of Windsor expressed concern about an apparently unusual number of cancers that had occurred in workers from South Essex Hall. In an initial meeting in late 2003 (where Dillon Consulting and University of Windsor representatives met), there was a particular concern expressed that two workers with similar job titles and closely located workstations had developed Waldenstrom's and multiple myeloma, respectively. The six cancers presented that gave rise to the initial concern are described below. b. Pilot Study Date of diagnosis Age at diagnosis Diagnosis Feb chronic myeloid leukemia Dec adenosarcoma lung large cell Nov pancreatic cancer Jul multiple myeloma May Waldenstrom's macroglobulinemia Jul Carcinoid In a preliminary, pilot study, we have verified the initial cancers of concern by running the six involved names through the Cancer Care Ontario (CCO) Registry. The Registry records all cancers that were diagnosed to residents of Ontario. Consent forms were designed and mailed to the potential study participants. All were signed and returned by the patient or surrogates. Of particular note are cases of multiple myeloma, Waldenstrom's macroglobulemia and chronic myeloid leukemia (CML). All three are disorders of blood cells originating in the bone marrow (see Literature Overview). c. Possible Exposures There had been concern for some time about ventilation and air quality in South Essex Hall. The University of Windsor first looked at the issue of air quality in the Essex Hall building (particularly the South wing) in The concerns centred on air quality and specifically a 1

12 concern regarding diesel particulates and metallic dust and mercury, as well as other dust exposures. There were no discussions at that time about a cancer study. In September of 2001, the University contacted Pinchin Environmental to perform the hygiene testing. The air monitoring was completed in February The results of the air monitoring showed levels below the set limits. There were however, some PCB and mercury present and, in fact, loose mercury found on the floor in one area (1). While diesel particulates were shown to be low, it should be pointed out that testing was done on only 3 days in February We would expect seasonal variability in diesel particulates. During smoggy periods of the heavy summer driving season one would expect to find, higher readings. More recent testing by Pinchin done in 2007 in mid summer, however, showed diesel particulates to be well below set limits (8). There is concern that the air quality may have been substantially poorer in the past, before some improvements were instituted. In the late 1990s, there were upgrades or additions of several fumehoods in South Essex Hall. Four labs had new exhaust systems installed. New HVAC units were also installed in two labs. While no general, pertinent occupational exposures can be verified, workers described the air quality as being very poor before the ventilation improvements were done in the 1990s, during an initial meeting with union representatives, and University of Windsor stakeholders. The building is located very close to the on ramp of the Ambassador Bridge. Due to heavy truck and auto traffic and slow speeds, exposure to exhaust, both diesel and gasoline, was thought by some workers to be very heavy, particularly in South Essex Hall. As well, there were several tool and die workers employed in South Essex Hall before Tool and die workers are exposed to metalworking fluids (MWFs) for which there is evidence linking them to several cancers (26). d. Rationale for Further Study Based on the pilot study, we thought there was sufficient cause to do further study. Our position was based on the following factors: 1. The pattern of recent cancers is suggestive. Particularly the fact that two rare cancers that may well be causally related occurred in two workers whose work stations were close together in similar job titles. Additionally, one of these cancers occurred in a 37 year old individual, an age at which this disease is exceedingly rare. 2. There is the possibility that before ventilation improvements were made in South Essex Hall, exposures may have been high due to poor ventilation and proximity to high levels of diesel and gasoline fumes as well as metal dust. 3. Some studies have found associations between diesel fumes and possibly gasoline fumes exposures and the development of multiple myeloma (3). 2

13 4. The concern that the University of Windsor has expressed and its resolve to clarify the matter. Given the probable exposures and their noted associations with some of the rare cancers, this concern is not unreasonable. 5. The non-invasive nature of the study that poses no risk to the health and little risk to privacy of the workforce. 3

14 B. Literature Overview a. Definitions and Descriptive Epidemiology Three rather uncommon cancers are of particular interest in this study. Multiple myeloma is a tumour of plasma cells, which are a particular type of white blood cell. These cells, that contain no haemoglobin, are made by bone marrow and help the body fight infection and other diseases (12). Normal plasma cells are derived from B-lymphocytes and are typically found within the bone marrow (12). B-lymphocytes are a type of white blood cell that secrete large amount of antibodies (immunoglobulin proteins) that circulate in the blood. Each plasma cell produces only one kind of antibody (monoclonal immunoglobulin) but groups of different plasma cells secrete many kinds of antibodies (polyclonal immunoglobulin) (12). Foreign invaders, normally viruses or bacteria stimulate lymphocytes to become a type of plasma cell that secretes polyclonal antibodies. The antibodies can then attack and neutralize foreign bodies. The term multiple myeloma denotes the condition where tumour cells are found in multiple sites within the bone marrow (12). Monoclonal multiple myeloma cells are overproduced so that they comprise 10 to 80 percent of the cells in the bone marrow in contrast to the 1 percent that these cells comprise of normal bone marrow (12). The result is localized bone destruction, anemia, reduced immunity to infection and kidney damage as well as other effects and symptoms. Waldenstrom's is very similar to multiple myeloma except that it does not produce the bone damage typical of multiple myeloma. Waldenstrom's arises when plasma cells and/or abnormal lymphocytes produce an excess amount of certain large antibodies called immunoglobulin M (20). Chronic myeloid leukemia (CML) is a cancer of the blood producing cells of the bone marrow (21). CML is also sometimes called chronic granulocytic, chronic myelocytic or chronic myelogenous leukemia. Leukemia cells do not function normally and cannot do what normal blood cells do, such as fight infection, thus making leukemia patients more prone to infection. Platelet problems result in leukemia patients being more likely to have unexpected bleeding and to bruise easily (21). CML is usually associated with a specific gene mutation in a chromosome called the Philadelphia chromosome (21). This mutation is not inherited however. It is acquired due to lifetime exposures. Ionizing radiation is the only established cause of the mutation, although it accounts for the minority of cases (21). Multiple myeloma is an uncommon cancer but CML is quite rare while Waldenstrom's is extremely rare. Recent Waldenstrom s incidence rates found in participating cancer registries in the United States were found to average approximately 4.9/1,000,000/year ( person-years) in white men (4). Only about one case is diagnosed per year for every 200,000 white men in the United States. 4

15 It is even rarer in younger people as most cases occur in those 60 or older. The case that developed in a South Essex Hall employee was notable for the young age at diagnosis of 37. The age specific rate for those under 45 was estimated to be less than.5/1,000,000 per year. Only about one case of Waldenstrom s was diagnosed for every two million white men per year in the United States under 45. Clearly, Waldenstrom s is extremely rare in younger men. Both Waldenstrom s and multiple myeloma show a similar, very steep increasing incidence with increasing age (13). In 2001, for every 100,000 white males there were only about 6 cases of multiple myeloma diagnosed in the USA and 1.9 cases of CML (24). Note that although it is uncommon, multiple myeloma occurs, in white men, at more than 10 times the rate of Waldenstrom's (13). Windsor-Essex CML crude incident rates (from 1986/1996 combined) were very high (calculated from CCO statistics). The CML rate was 6.38/100,000/year. Notice that this is more than 3 times the United States national rate of The Ontario crude CML rate was similar to the United States rate at 2.20/100,000/year. The 1986/1996 crude incidence rate of multiple myeloma in Ontario men was 6.35/100,000/year. This is just slightly higher than the recent United States rate. The corresponding rate for Windsor-Essex 1986/1996 was found to be 6.38/100,000/year. While multiple myeloma incidence rates were very similar in Ontario and Windsor, the CML rates were very different. The Windsor-Essex CML rates, however, were very volatile, as expected, being about three times higher in 1996 than in Therefore, the Windsor- Essex rates are not statistically stable for this cancer. Age-adjusted Waldenstrom s incidence rates in the United States over a 7 year period from 1988 to 1994 were found to be higher for whites than for blacks in contrast to the racial pattern found in multiple myeloma where blacks have about double the rate of whites (13). Since both multiple myeloma and Waldenstrom's are thought to be derived from B cells at a late state of maturation, the racial pattern disparity is interesting (13). Specifically, if multiple myeloma and Waldenstrom s have similar causation we would expect similar racial risk patterns for both diseases. The apparent contrasting racial patterns between myeloma and Waldenstrom s could be due to surveillance bias. Since Waldenstrom s is very rare and not fully understood, it is prone to under-ascertainment and diagnostic errors. The ascertainment may be lower for blacks who generally have access to poorer medical care in the United States. b. Etiology Comparatively little is known about either the risk factors or the incidence of Waldenstrom's (13). It was only discovered in 1944 and was not a reportable disease in the United States until 1988 (13). The only readily available incidence data comes from two American studies that look at overlapping data (13, 4). The more comprehensive study, referred to earlier, compiled reported Waldenstrom's incidence data gathered from 11 population 5

16 based Cancer Registries in the United States. They found a total of 624 cases between 1988 to 1994 inclusive (13). Since myeloma and Waldenstrom s are closely related conditions, it is reasonable to assume that they probably share, at least some causal factors. Supportive evidence at this point is limited, because our knowledge is mostly inconclusive about the etiology of these diseases, particularly Waldenstrom s. Although, the causes of multiple myeloma and Waldenstrom s are for the most part, not clear, ionizing radiation exposure has been found to be a risk factor for multiple myeloma in follow-up studies of atomic bomb survivors (17) and the only known risk factor for CML (21). CML is clearly distinct from the other two diseases. The main common factor is that like Waldenstrom s and myeloma, CML arises in blood cells in the bone marrow. As mentioned earlier, however, in contrast to the other two conditions, CML has a specific and significant genetic component Railroad workers have shown higher incident rates of multiple myeloma in several studies (5, 18). Amongst the suspected exposures are diesel fumes. Other suspects are benzene and creosote. Flodin et al. found elevated rate ratios for occupational exposures to engine exhausts, creosote and fresh wood (19). Diesel fumes have been implicated in several other studies including Lee et al. (3). When adjusted for other factors, Lee found an RR of 1.3 (30% increased risk) that was statistically significant at the 95% level. However, there was no dose-response found in this study, which limits the establishment of firm conclusions. Bezabeh et al. reviewed several studies that investigated the possible relation of engine exhaust exposure to multiple myeloma and concluded that they suggest that there is an association. Of the seven studies that they reviewed, all but one found an Odds Ratio of more than one (suggests association) although only one was statistically significant at the 5% level (22). The literature suggests that diesel fumes are a probable cause of multiple myeloma, but the relationship is not firmly established. An American case-control study found increased multiple myeloma rates in men previously employed as painters (solvent exposure) or in agriculture. Agricultural workers who were known to be exposed to pesticides were at particularly high risk (14). Their study lends support to previous studies that have found similar associations (14). There is biological plausibility for benzene being causally related to the rare cancers of interest here. Benzene metabolites are destructive to the bone marrow (11). A metaanalysis found a statistically significantly increased risk of multiple myeloma in those exposed to benzene (25). 6

17 C. Methods This is a historical cohort study. This means that a group of workers were identified by past records and followed forward in time, to trace cancer development. Standardized Incidence Ratios (SIRs) were calculated on the historical cohort of workers who started work in Essex Hall at any time between 1955 and Standardized Incidence Ratios (SIRs) were constructed for total cancers and individual cancers (or related groups of cancers) where numbers permitted. Analyses was done for both males and females, although the small numbers of females necessitates that both the analyses and interpretation concentrate on the male workers. The numbers were too small to allow meaningful analyses of individual cancers in females. Only five female cancers developed, each in different sites. The person-years partitioned by age and sex were calculated using the human resource data base of workers in Essex Hall. Analyses were done using both Windsor-Essex 1986/1996 and Ontario age-specific cancer incident rates from to calculate the expected number of cancers. The observed cancers were compared to the expected cancers using the SIR as follows: SIR = observed/expected where: observed - the number of cases of the cancer of interest that developed in the work cohort found by linking the Essex Hall cohort with the CCO Cancer Registry expected - the number of cancers that would have occurred in the worker population if they were getting cancer at the same rate as the standard population Therefore an SIR of 1 means that the worker population is getting cancer at the same rate as the standard population (Windsor-Essex or province of Ontario). We say that they are getting cancer at the expected rate. An SIR of 2 means that the worker population is getting cancer at twice the expected rate. They developed two cancers for every one expected. This signifies, of course, that there may be a problem. An SIR of ½, on the other hand, means that they worker population is developing cancer at only ½ the rate of the standard population. A SIR of less than one generally, but not always, signifies a favourable situation. Sometimes the expected number of the disease in question should be less than the standard population number, in the absence of an occupational 7

18 exposure. This occurs when the workforce is at lower risk than the general population with respect to the disease of interest. (see Healthy Worker Effect). The SIR is referred to as standardized because it indirectly adjusts (takes into account) for the age distribution of the worker population in the calculation of the expected rates. Ninety percent approximate confidence intervals were calculated and presented for all SIRs (6). All analyses were done separately for those who worked in South Essex Hall and those who worked in the rest of Essex Hall. If South Essex Hall had poorer ventilation in the past with resultant greater exposures then we may expect South Essex Hall workers to have high cancer rates. Similarly, analyses were done separately for those who started well before the fume hoods were updated (started before 1985 or 1990) and for those who started work in 1985 or 1990 or after. If there were significant ventilation problems and they caused significant exposures then we would expect (other factors being equal) more cancer to occur in the earlier start date group than in the standard population. For many in the post 1985 start group date and most in the post 1990 start date group, insufficient time has elapsed for many work related cancers to be diagnosed. That is, if work related cancers were a problem for this group there may not have been sufficient elapsed time for many of the cancers to manifest. This is particularly true for solid tumours. Solid tumours, such as lung cancer may take up to 25 years to be diagnosed after initial exposure to the carcinogen. Statistical significance at the 5% and 10% levels will be used as a rough guide only to determine if an unusual cancer experience occurred in this population (see Burden of Proof). Statistical significance is most relevant when one is testing one question with one statistical test. When several tests are performed in one study, it is referred to as multiple comparisons. Multiple comparisons increase the probability of chance findings (false positives) beyond the stated risk (p-value). Even if a result is statistically significant, there is still a real probability that the finding was a false one. On the other hand, false negatives may occur because of the low statistical power. As well, there are several possible biases that will generally bias the results towards the null (finding no effect). The patterns of any elevated cancer rates as well as the purely statistical aspects of the results can be used to separate results likely due to chance from those that are more suggestive of problems. a. Study Population The study population was to comprise all of those who started work in Essex Hall during the time period of 1955 to Preliminary data analyses showed that the work roster was incomplete. Those who began work before 1985 were included in the roster only if they were still actively working during 1985 or thereafter. These problems arose because only 8

19 current workers were transferred to an updated human resources database in Those who had begun work before 1985 but were not on the current payroll at that time, were not available for study. Clearly, the incomplete roster for those starting work before 1985 is biased in favour of inclusion of long-term workers. For example, if a worker started work in Essex Hall during 1968 and ended employment (in that area or the University) before 1985, they would not be included in the study cohort. If, however, they started work in 1968 and were still working in Essex Hall in 1985, they would be included. The roster was provided to us by the University of Windsor. Total person-years of exposure were calculated by subtracting the starting working date in Essex Hall from January 1, This date was chosen because CCO's registry was current, although not necessarily complete, up to the end of Person years were partitioned by age for each worker. The approximate breakdown of person years is displayed in Table 2. Exclusions from the study population Students were not included in the study if their role at Essex Hall of the University of Windsor was solely as a student. If a student subsequently became a part-time or full-time employee in Essex Hall, they would be enrolled in the study on their employment start date in Essex Hall. Students were not included because it was judged that student record limitations would make it extremely difficult to track exposure to Essex Hall. As is common with studies of this kind, this study has generated considerable publicity and interest. As a result, several people have called the University of Windsor wishing to be included in the study, who were eligible for the study but whose record was missing. As mentioned earlier, many records are not available for those who did work in Essex Hall during the study period. These people were not included because those who called to be included in the study may differ in relevant ways from eligible, but not included people (or their surrogates) who heard about the study but did not contact the University. More specifically, it is very possible that those who developed cancer may be more motivated to be included in the study than those who did not. Therefore, these people were excluded to limit the possible serious bias that their inclusion would cause. Cancers were only counted if they were diagnosed after the work start date. Several cancers were not counted because they were diagnosed before the work start date in Essex Hall. Of these, one was a myeloma. Records showed that this individual was a student years earlier and that the myeloma occurred after his student starting date. Although this myeloma did not count, because it did not meet the set criteria and to count it would have introduced bias, nevertheless it is a case that could possibly be related to exposures in South Essex Hall. The student records are not precise enough to document exposure in Essex Hall. 9

20 D. Limitations a. General 1. This study utilizes occupational epidemiology, a field that investigates whether occupational exposures are associated with subsequent excess rates of disease. SIR studies, such as this one, are referred to as ecological because we have no information on non-occupational risk factors in individuals, such as smoking, family history, etc. Occupational ecological studies are, therefore, blunt tools. As is usually the case in these situations an investigation was initiated by a belief among workers that their colleagues in some worker subgroup were experiencing more than the normal amount of cancer. A cancer cluster is an excess rate of cancer or of a cancer type (types) over what would normally be expected in the worker population. It may be due to an occupational exposure to a carcinogen, characteristics of the workers (genetic or lifestyle), other common environmental exposures or to chance. Traditional epidemiologic and statistical methods are not readily applicable to the investigation of clusters because of the unique problems associated with their analysis and interpretation Part of the problem is the bias associated with the choice of the particular work group to study. For example, assume that there are no workplace carcinogens and additionally that all workers have the same chance of getting cancer. Then if there were 100 workplaces in Canada of the same size, we would expect, on average, 5 to develop a statistically significant excess of cancer. This follows from statistical probability theory. More attention would presumably be given to the workplaces with high cancer rates. Looked at in isolation, these workplaces would appear to be problem areas. However, we know, in this example, that the high cancer rates found were due to chance or natural variation. Some workplaces will have higher cancer rates and some lower cancer rates, in the absence of any carcinogens. When we study a workplace that has a high cancer rate(s), it is important to consider these statistical issues. The problem lies in separating high cancer rates that are likely due to chance or other factors from those with workplace related causation. It should be clear that a statistically elevated cancer rate, in itself, is not cause for alarm. Working in Essex Hall, was used as an inexact surrogate measure for any occupational exposures that may have occurred there. Since there is no information on individual exposures, there is no way to control for confounding for individuals because we do not know what other factors besides occupational ones may have caused cancers. Certainly many other common causes are acting besides the one(s) of interest in this study. For these reasons, firm conclusions regarding cause and effect for such studies are generally not possible. Even determining whether a disease is associated with an occupational group may be difficult due to many biases and limitations, some of which are described in this section. 10

21 Statistical results can only be used as a guidepost. Since a number of independent SIRs were calculated, more than 10% (at the 90% confidence level) would be expected to be statistically significant even if Essex Hall workers were getting cancer at exactly the expected rate. Stated differently, even if there were no cancer problems in Essex Hall, some of the results would be expected to be statistically significant if a number of SIRs were calculated. On the other hand, small numbers result in very low statistical power (ability to detect SIRs as statistically significant that are truly elevated). Therefore, elevated but non statistically significant results may not provide reason for comfort. On interpretation of this pattern, reasonable people may disagree. The calculation of SIRs is an exact science. The interpretation of the pattern of a number of SIRs in a population is, however, more of an art. We are dealing with cancer, which for the most part involves very long periods from exposure to diagnosis. This period between initial exposure and diagnosis will vary by cancer. It is difficult to assign causation for a cancer to an exposure that may have occurred 25 years ago. These problems are less important for some of the cancers such as leukemia that have a shorter induction period. It becomes obvious that one will not uncover excesses if one is looking in the wrong time window. Many leukemias may have short latency periods of less than 10 years. However, if an employee started work at Essex Hall and developed lung cancer 4 years later, it is almost certain that Essex Hall exposures did not cause the lung cancer. We know this because the minimum time needed for lung cancer to develop after initial exposure is much greater than 4 years. The expected pattern of excess rates in time is one of the tools we can employ to separate perhaps spuriously elevated rates from ones that require further scrutiny. b. Study Specific 1. Power considerations Power refers to the ability to detect a true excess of cancer of a specific amount. A limitation of the study will be the small population size. There were 799 workers in the study cohort of workers. The nearly 600 males who serve as the focus of the study, however, provide a more substantial total of over 9000 person-years of exposure. This number should be adequate for meaningful analyses, since SIRs are efficient statistically for small population studies. The efficiency of SIR studies is exemplified in the results where only two cases of multiple myeloma were sufficient to produce statistically significance results at the 90% confidence level. Epidemiology utilizes person-years as the denominators when calculating rates, in order to take into the amount of time that a person was followed. For example, one person followed for 5 years would provide 5 person-years of observation. Two people followed for 10 years would provide 20 person-years of observation. Ann employee who started work at the beginning of 1980 would provide 27 person-years of observation, since the study observation ended after

22 No account was made for induction periods in the analyses. That is, all cancers that were diagnosed after the starting date of work in Essex Hall were counted. Most of these cancers occurred long after the starting date in any case. For example, both multiple myelomas were diagnosed after more than 10 years of employment in Essex Hall. The power in this study will generally be very low for rare cancers and for sub-analyses involving more common cancers. Power can be thought of as related to the quality and quantity of the evidence available, similar to evidence in a criminal legal trial. If there is not a large quantity of evidence and/or the evidence is unreliable, (bias) then the defendant is likely to be found not guilty. That does not at all imply that he/she is innocent. Similarly, when there are small numbers and little scientific information available in epidemiological studies, the results are often found to be not statistically significant. That means that we did not find that there was an excess of cancer beyond a reasonable scientific doubt. Reasonable doubt in science is quantified (and chosen) by the significance level. If the significance level is 5% (confidence level of 95%) then there is a 5% chance we will be wrong when we say that there is an excess of cancer. Note that results may not be statistically significant because there is truly no real increase in cancer or because there was not enough evidence (low statistical power). 2. Data base irregularities Probably more important than the lack of statistical power are the data base irregularities that were briefly discussed earlier. A sizable portion, most likely, the majority of the cohort that started worked in Essex Hall between 1955 and 1985 have not been transferred to the present database. There are two problems with this. The more obvious problem is that a lot of important information is not available for study. If the workers, for which we have no data, differ in pertinent ways from the early Essex Hall workers for whom we have information, then the problem is much more serious. This situation may result in study bias. For example, imagine that workers who had some health related problems caused by or aggravated by exposures in South Essex Hall, may have been more likely to leave work sooner than those who did not react adversely. If these workers were also more likely to develop cancer due to Essex Hall exposures, then our study would underestimate cancer risks. That is because those most likely to develop cancer would be missing from our database, since they would not continue working in Essex Hall until This scenario is very unlikely because any exposures in Essex Hall were not described as noxious to the point as to cause immediate symptoms. Most likely, the early workers included in the database would not differ markedly in regards to cancer risk than those excluded. In that case, there is not bias in the study, although the statistical power would be reduced due to the smaller number of workers followed and evaluated. The database was constructed for Human Resources purposes without regard for possible scientific analyses. By definition, one would expect it to be lacking, somewhat for a study of this kind. 12